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| United States Patent |
5,292,532
|
|
Bombart
|
March 8, 1994
|
Aqueous antifungal vaginal douche
Abstract
An aqueous vaginal douche which is at most marginally effective against
bacteria but which includes a fungicidal/fungistatic agent to rid the
vaginal zone of yeasts. The douche may include a penetrating agent and/or
an adherent to hold the fungicidal/fungistatic agent to the vaginal
tissues. The douche is inserted into the vagina by means of a nozzle or
the like. The douche may incorporate a carrier or solvent for the
fungicidal/fungistatic agent and may further include a preservative.
| Inventors:
|
Bombart; Felice (240 East 27th Street, Apt. 6J, New York, NY 10016)
|
| Appl. No.:
|
958609 |
| Filed:
|
October 8, 1992 |
| Current U.S. Class: |
424/405; 424/430; 424/433 |
| Intern'l Class: |
A01N 025/04; A01N 043/16; A01N 043/52 |
| Field of Search: |
424/422,426,430,434,405,433
|
References Cited
U.S. Patent Documents
| 4895727 | Jan., 1990 | Allen | 424/642.
|
| 5043155 | Aug., 1991 | Puchalski et al. | 424/78.
|
| 5158774 | Oct., 1992 | Inman | 424/430.
|
Other References
Remingtons Pharmaceutical Sciences, Mack Publishing Co. (1988) Edition.
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Guy; Neil
Attorney, Agent or Firm: Seide; Rochelle K.
Parent Case Text
This is a continuation of copending application Ser. No. 07/752,161 filed
on Aug. 21, 1991, abandoned, which in turn, is a continuation, of
application Ser. No. 633,224, filed Dec. 21, 1990 now abandoned.
Claims
What is claimed is:
1. An aqueous antifungal vaginal douche composition consisting essentially
of an antifungal agent selected from the group consisting fomiconazole,
clotrimazole, ketoconazole and nystatiin in an amount effective to kill
and/or inhibit the growth of yeasts or fungi in the vagina, a penetrating
agent selected from the group consisting of ethoxylated alcohols,
ethoxylated alkylphenols, ethoxylated fatty acids, ethoxylated castor oil,
alkanolamides, ethylene glycol/propylene glycol copolymers, ethoxylated
sorbitol, ethoxylated sorbitol esters, ethoxylated glycerol esters, alkyl
sulfosuccinates, alkyl sulfonates, alkyl sulfates, alkyl aryl sulfonates,
alkyl aryl sulfates, phosphate esters and betaines in an amount effective
to enhance penetration of the antifungal agent into vaginal tissue, an
adherent agent selected from the group consisting of arabic, align, guar,
tragacanth and xanthan gums, pectin, dextran, sodium carboxymethyl
cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxyethyl methyl cellulose, polyvinyl alcohol, polyacrylic
acid and acidic gums in an amount effective to enhance adherence of the
antifungal agent to vaginal tissue and a carrier or solvent selected from
the group consisting of polyethylene glycols, polyoxyethylene glycols,
polypropylene glycols and polyoxypropylene glycols, wherein said douche
composition has a pH of about 5.5. to 8.5 and will not disturb the normal
bacterial balance in the vagina.
2. The douche composition of claim 1 wherein the antifungal agent is
miconazole.
3. The douche composition of claim 1 wherein the antifungal agent is
clotrimazole.
4. The douche composition of claim 1 wherein the antifungal agent is
ketoconazole.
5. The douche composition of claim 1 wherein the antifungal agent is
nystatin.
6. The douche composition of claim 1 wherein the effective amount of
antifungal agent is between 0.03-3.0 weight percent of the composition.
7. The douche composition of claim 1 wherein the penetrating agent is a
nonionic agent selected from the group consisting of ethoxylated alcohols,
ethoxylated allyl phenols, ethoxylated fatty acids, ethoxylated castor
oil, alkanolamides, ethylene glycol/propylene glycol copolymers,
ethoxylated sorbitol, ethoxylated sorbitol esters and ethoxylated glycerol
users.
8. The douche composition of claim 1 wherein the penetrating agent is an
anionic agent selected from the group consisting of lakyl sulfo
succinates, alkyl sulfonates, alkyl sulfates, alkyl aryl sufonates, alkyl
aryl sulfates, phosphate esters and betaines.
9. The douche composition of claim 1 wherein the adherent agent is a
natural gum selected from the group consisting of arabic, align, guar,
tragacanth and xanthan gums, pectin and dextran. pH of about 5.5. to 8.5
and will not disturb the normal bacterial balance in the vagina.
10. The douche composition of claim 1 wherein the adherent agent is a
modified natural gum selected from the group consisting of sodium carboxy
methycellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, and hydroxyethyl methyl cellulose.
11. The douche composition of claim 1 wherein the adherent agent is a
synthetic gum selected from the group consisting of polyvinyl alcohol and
polyacrylic acid.
12. The douche composition of claim 1 wherein the carrier has a molecular
weight between 200-2000.
13. The douche composition of claim 12 wherein the carrier has a molecular
weight of 400.
Description
FIELD OF INVENTION
This invention relates to vaginal douches and more particularly to vaginal
douches incorporating therein fungicidal/fungistatic (fungicidal and/or
fungistatic) agents. This invention also relates to methods for preparing
and utilizing vaginal douches which include fungicidal/fungistatic agents.
BACKGROUND
There are three types of compositions available that can be hygienically
administered to the vaginal zone. The simplest is essentially water acting
as a cleansing agent. A second type contains povidone-iodine. This product
is effective against bacteria, but not against fungi. The presence of
normal bacterial flora in the vagina is desirable, should not be reduced,
and does not cause discomfort. The presence of fungal overgrowth in the
vagina is undesirable causing discomfort and infection. Therefore,
povidone-iodine is considered to be unsuitable for preferred hygienic
administration to the vaginal area.
A third type of treatment consists of pharmaceutically acceptable
fungicidal/fungistatic compositions which are effective. However, the
methods of application for these products are cumbersome and
insufficiently effective. The products that are supplied in tablet form
require insertion into the vagina with the aid of a mechanical device. The
tablet thereafter disintegrates and is distributed throughout the vagina
to come in contact with the fungi in order to be effective. This method of
treatment is not very effective. Miconazole nitrate supplied in a cream
formulation is also cumbersome to apply vaginally and the difficulty of
thorough distribution to all tissue surfaces reduces its effectiveness.
In reviewing prior art patents, relative to the preparation of this
application there were uncovered U.S. Pat. Nos. 3,011,946 (Bartner et al)
; 4, 195, 172 (Falkowski et al) and 4,102,998 (Gutnick).
The Bartner patent develops an aqueous solution of nystatin which is highly
soluble in an aqueous solution of a soluble saccharin. The discovery
discloses that the incorporation of benzyl alcohol into the solution
imparts an improved solubility to the nystatin. According to the patentee,
nystatin preparations are parenterally administered and administration is
intended to be by injection in an intramuscular or intravenous fashion.
This is different from the administration of a vaginal douche by means of
a nozzle or the like.
The Falkowski patent relates to salts of various compounds including
nystatin which are of very high water solubility. The resulting compounds
are said to exhibit antifungal activity. This patent relates to injectable
solutions and not to the administration of douches. One of the specified
nystatin salts derived is N-methylglucamine salt of the N-glycosyl
derivative of nystatin.
The Gutnick patent relates to a process for the prevention of venereal
disease. It embodies a metal intrauterine contraceptive device for
medication, which is released gradually into the vagina and the lower end
of the uterus over a prolonged period of time. This patent relates to
antibacterials and antibiotics and the device includes a magnet. Reference
is also made to antifungal activity in other places in the text of this
patent, but nystatin is referred to as an antibiotic with antifungal
activity. No reference is made to a water soluble nystatin.
None of the known prior art nor the forgoing patents relates to the
preparation of a fluid douche especially suited for killing or inhibiting
fungi such as yeast in the vaginal zone while being at most marginally
effective with respect to bacteria.
SUMMARY OF INVENTION
It is an object of the invention to provide an improved vaginal douche.
It is another object of the invention to provide an improved vaginal douche
capable of eradicating or minimizing the presence of fungi.
It is still another object of the invention to provide an improved aqueous
vaginal douche capable of eradicating fungi while being at most marginally
effective relative to bacteria of the type normally found in the vaginal
zone.
It is still another object of the invention to provide an improved vaginal
douche and methods for the use thereof based on recognition of the facts
that, 1) it is harmful to remove the bacteria from the vaginal zone and 2)
that it is of substantial importance to eradicate fungi such as yeast in
the vaginal zone.
In achieving the above and other objects of the invention, there is
provided a method comprising effecting hygienic cake of a vaginal zone by
introducing into the vaginal zone a fluid douche into which has been
incorporated a fungicidal/fungistatic agent. More particularly the
fungicidal/fungistatic agent which is employed in accordance with the
invention has at most a marginal effectiveness against bacteria especially
of the type normally found in the vaginal zone.
As features of the invention, the method thereof further comprises
enhancing the penetration of the douche into the vaginal zone by
incorporating into the douche a penetrating agent. According to a further
feature of the invention there is comprised in the method thereof the
enhancing of adhering of the fungicidal/fungistatic agent to the tissue in
the vaginal zone by incorporating into the douche an adherent adapted to
retain the fungicidal/fungistatic agent in the vaginal zone.
Preferably in accordance with the invention the fluid douche is prepared
with water as the fluid whereby to form an aqueous douche. Preferably the
adherent is a gum such as for example selected from the group consisting
of arabic, align, guar, tragacanth, pectin, dextran and xanthan. The
aforesaid gums are natural gums. A further group which is useful in
providing an adherent in accordance with the invention is a modified
natural gum. These may be selected from the group consisting of sodium
carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, and hydroxyethyl methyl cellulose. The gum
employed in accordance with the invention may also be a synthetic gum such
as polyvinyl alcohol, polyacrylic acid and polyvinyl pyrrolidine. Acidic
gums may be used as is or as their salts, for example, formulated with
sodium or potassium hydroxide, or organic amines such as triethanol amine,
monoisopropanol amine or di-(2-ethyl hexyl) amine.
The penetrant which is employed may be a nonionic agent selected from a
group consisting of ethoxylated alcohols, ethoxylated alkyl phenols,
ethoxylated fatty acids, ethoxylated castor oil, alkanolamides, ethylene
glycol/propylene glycol copolymers, ethoxylated sorbitol, ethoxylated
sorbitol esters and ethoxylated glycerol esters. The penetrant may also be
an anionic agent selected from a group consisting of alkyl
sulfosuccinates, alkyl sulfonates and sulfates, alkyl aryl sulfonates and
sulfates, phosphate esters and betaines.
In accordance with the invention the fungicidal/fungistatic agent may be of
various types. Some examples which are employed in accordance with the
invention include miconazole,
1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)
methoxy]ethyl]-1H-imidazole; clotrimazole,
1-[(2-chlorophenyl)diphenylmethyl)-1H-imidazole; ketoconazole,
cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-l-ylmethyl)-1,3-
dioxolan-4-yl]-methoxy]phenyl]piperazine; and nystatin.
According to the invention the dispersion and solution of the
fungicidal/fungistatic agent in water may be enhanced by incorporating a
carrier or solvent into the douche. The carrier may be for example
polyethylene glycol or polypropylene glycol and preferably one having a
molecular weight range from about 200-2000.
Preferably the douche will be adjusted to a pH of about 5.5 to 8.5. In
addition there may be incorporated a preservative in the douche such as
for example methylparaben or propylparaben. The douche of the invention is
introduced into the vaginal zone via a nozzle inserted therein.
This invention also relates to the provision of a product. This product
comprises a vaginal douche including a fungicidal/fungistatic agent having
at most a marginal effectiveness against bacteria. The vaginal douche in
accordance with the invention is an aqueous douche. Preferably the aqueous
douche includes a penetrating agent and/or an adherent of the above noted
type.
The above and other objects, features, and advantages will become apparent
from the following detailed description of some preferred embodiments
thereof.
DETAILED DESCRIPTION
The purpose of this product is to provide prompt hygienic direct relief
from vaginal itch and irritation caused by fungal overgrowth and fungal
types of infection. This preparation is in the form of a douche for easily
administered direct refreshing application, providing thorough
distribution, adherance and penetration of the vaginal zone.
Vaginal itch and irritation secondary to fungal overgrowth is a very common
problem plaguing approximately 50% of the female population. This type of
vaginitis is caused by fungal overgrowth.
A mild amount of fungal overgrowth will cause persistent itch, irritation,
and foul smelling discharge. A substantial amount of fungal overgrowth
causes unbearable constant itching, severe inflammation and profuse foul
smelling discharge, therefore an enormous amount of discomfort. Fungal
infections are communicable.
In normal amounts, vaginal bacteria keeps in check or limits fungal
overgrowth. A decrease in the amount of normal vaginal bacterial flora
will allow fungal overgrowth.
Altered and/or decreased vaginal bacterial flora is caused by 1) antibiotic
therapy, 2) chemotherapy, 3) altered immunologic conditions such as AIDS,
and De George Syndrome, 4) cancer, 5) stress and 6) poor nutrition. Fungal
overgrowth is also caused by altered metabolic states such as diabetes
mellitus. For those females with diabetes mellitus, fungal overgrowth in
the vagina is a chronic problem and requires constant treatment throughout
one's lifetime. A significant amount of healthyll females also have
chronic yeast overgrowth of unknown etiology.
Presently on the market there is no douche that can treat or decrease
fungal overgrowth in the vagina. On the contrary, aqueous products or
douches used in the vagina can cause a decrease in normal bacterial flora,
altering the normal balance between bacteria and fungi, thereby promoting
fungal overgrowth.
There is also on the market a douche containing a povidone-iodine solution
which is bactericidal, thereby decreasing the amount of bacteria and
directly promoting fungal overgrowth.
In prescription form there exists treatments with pharmaceutically
acceptable fungicidal/fungistatic compositions. However, the method of
application for these products is cumbersome and insufficiently effective.
The products are supplied in tablet and cream form and require insertion
into the vagina with the aid of a mechanical device. The tablet by itself
must then disintegrate and distribute throughout the vagina to come in
contact with the fungi in order to be effective. This method of treatment
is ineffective. Miconazole nitrate supplied in a cream formulation is also
cumbersome to apply vaginally using a mechanical device and the difficulty
of thorough distribution to all tissue surfaces reduces its effectiveness.
The invention overcomes the above deficiencies by providing an
uncombersome, refreshing, effective product in a form that is easy to use.
The product is formulated to be rapidly distributed throughout the vagina
and vaginal zone for purposes of reaching all tissue surfaces. Ingredients
are, in accordance with the invention, included in the composition to
enhance penetration, and adherence, to-the tissue surfaces in the vaginal
zone.
Pharmaceutically acceptable fungicidal/fungistatic agents for the product
include miconazole, 1-[2-(2,4-dichlorphenyl)-2-[(2,4-dichlorophenyl)
methoxy]ethyl]-1H-imidazole; clotrimazole, 1-[(2-chlorophenyl)
diphenylmethyl)-1-Himidazole; ketoconazole,
cis-i-acetyl-4-[4[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-d
ioxolan-4-yl]-methoxy]phenyl]piperazine; and nystatin. These substances are
known for their fungicidal/fungistatic properties. The first three are
synthetic substances; the last, nystatin, is a polyene antibiotic obtained
from a microorganism culture. Their effectiveness against bacteria is
marginal and, therefore, they will not disturb the normal bacterial
balance in the vagina.
The composition of the invention is enhanced by incorporating a gum to
provide adherence to the vaginal tissues. Natural gums may be used such as
arabic, align, guar, tragacanth, pectin, dextran, and xanthan. Modified
natural (semisynthetic) gums may be used such as sodium carboxymethyl
cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose and hydroxyethyl methyl cellulose. Synthetic gums such as
polyvinyl alcohol, polyacrylic acid and polyvinyl pyrrolidine may also be
used. Acidic gums may be used as is, or as their salts. For example, these
gums can be formulated with sodium or potassium hydroxide, or organic
amines such as triethanol amine, monoisopropanol amine or di-(2-ethyl
hexyl) amine.
A penetrant is incorporated to hasten and improve the penetration and
adherence of the fungicide to the tissue surfaces. Nonionic penetrants may
be used such as ethoxylated alcohols, ethoxylated alkyl phenols,
ethoxylated fatty acids, ethoxylated castor oil, alkanolamides, ethylene
glycol/propylene glycol copolymers, ethoxylated sorbitol, ethoxylated
sorbitol esters and ethoxylated glycerol esters. Anionic penetrants may
also be used such as alkyl sulfosuccinates, alkyl sulfonates and sulfates,
alkyl aryl sulfonates and sulfates, phosphate esters and betaines.
The compositions also contain a carrier or solvent for the components to
assist in the dispersion and solution of the ingredients in water for
efficient introduction and distribution within the vagina. No mechanical
device is required as with the use of a fungicide in tablet or cream form.
Suitable carriers are polyethylene glycols (PEG), also known as
polyoxyethylene glycols (POE), and polypropylene glycols (PPG), also known
as polyoxypropylene glycols (POP). Grades in the molecular weight range
200-2000 are suitable. A 400 molecular weight grade is preferred.
Minor percentages (for example, up to about 1%) of other components may be
included in the following examples to render the compositions more
pharmaceutically desirable. The pH may be adjusted to 5.5-8.5 as desired
with tactic acid, citric acid, their sodium salts, or similar substances.
Preservatives may be added as desired, such as methylparaben,
propylparaben or similar substances. Suitable fragrances may be added as
desired.
______________________________________
EXAMPLE 1
Wt %
______________________________________
Miconazole 1-3
Tragacanth 1-3
*Nonyl phenol polyethylene glycol
1-3
Polyethylene glycol 400
97-91
100
______________________________________
*Tergitol NP10 (Union Carbide Corp) containing 10.5 mols of ethylene
oxide.
All ingredients are mixed at 20-50 degrees Celsius producing a solution or
dispersion in the glycol. 4-5 parts of the product are mixed with 100-150
parts of water producing a concentration of 0.025-0.15% clotrimazole for
vaginal treatment. Insertion into the vaginal zone is by means of a nozzle
or the like.
The following Examples 2-6 are prepared it the same manner as that used for
Example 1.
______________________________________
Wt %
______________________________________
EXAMPLE 2
Clotrimazole 1-3
*Polyacrylic acid 1-3
Triethanol amine 1-3
**Ethoxylated castor oil
1-3
Polyethylene glycol 400
96-88
100
EXAMPLE 3
Ketoconazole 1-3
Pectin 1-3
Nonyl phenol polyethylene glycol
1-3
Polyethylene glycol 400
97-91
100
EXAMPLE 4
Nystatin 1-3
Dextran 1-3
Ethoxylated castor oil
10-30
Polyethylene glycol 400
88-64
100
EXAMPLE 5
Clotrimazole 1-3
Ethoxylated castor oil
10-30
Polyethylene glycol 400
89-67
100
EXAMPLE 6
Clotrimazole 1-3
Polyacrylic acid 1-3
Triethanol amine 1-3
Polyethylene glycol 400
97-91
100
***EXAMPLE 7
(A) Clotrimazole 1-3
Polyethylene glycol 400
99-97
100
(B) Algin 1-5
Nonyl phenol polyethylene glycol
.01-.5
Water 98.99-94.5
100
****EXAMPLE 8
(A) Clotrimazole 1-3
Ethoxylated castor oil
99-97
100
(B) Arabic 1-5
Water 99-95
100
##EXAMPLE 9
Clotrimazole .03-.2
Polyacrylic acid .03-.2
Triethanol amine .03-.2
Ethoxylated castor oil
3-20
Water 96.91-79.4
100
****EXAMPLE 10
(A) Clotrimazole 1-3
Ethoxylated castor oil
99-97
100
(B) Polyacrylic acid .03-.2
Triethanol amine .03-.2
Water 99.94-99.6
100
______________________________________
*Carbopol 934; Goodrich Chemical Co.
**POE (40) Castor oil; Trylox CO40, Code 5909; Henkel Corp., Emery Group.
***(A) is prepared by mixin the ingredients at 20-5 degrees Celsius. 4-5
parts of (A) are added and mixed with 100-150 parts of (B) at ambient
temperature and used immediately as a vaginal douche.
##All ingredients are mixed at 20-50 degrees Celsius.
****Prepared and used as Example 7.
There will now be obvious to those skilled in the art many modifications
and variations of the method and products set forth above. These
modifications and variation will not depart from the scope of the
invention defined by the following claims.
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